Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy
Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved..
PURPOSE: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses.
METHODS: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics.
RESULTS: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts.
CONCLUSION: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia.
| Errataetall: |
ErratumIn: Genet Med. 2023 Oct;25(10):100961. - PMID 37650884 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Genetics in medicine : official journal of the American College of Medical Genetics - 24(2022), 10 vom: 01. Okt., Seite 2079-2090 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Park, Joohyun [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.4.19.12 |
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| Anmerkungen: |
Date Completed 11.10.2022 Date Revised 31.08.2023 published: Print-Electronic ErratumIn: Genet Med. 2023 Oct;25(10):100961. - PMID 37650884 Citation Status MEDLINE |
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| doi: |
10.1016/j.gim.2022.07.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM345052765 |
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| 100 | 1 | |a Park, Joohyun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy |
| 264 | 1 | |c 2022 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 11.10.2022 | ||
| 500 | |a Date Revised 31.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Genet Med. 2023 Oct;25(10):100961. - PMID 37650884 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved. | ||
| 520 | |a PURPOSE: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses | ||
| 520 | |a METHODS: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics | ||
| 520 | |a RESULTS: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts | ||
| 520 | |a CONCLUSION: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Gene burden | |
| 650 | 4 | |a Proteomics | |
| 650 | 4 | |a Spastic ataxia | |
| 650 | 4 | |a UCHL1 | |
| 650 | 7 | |a UCHL1 protein, human |2 NLM | |
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